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Gene Review

NCK2  -  NCK adaptor protein 2

Homo sapiens

Synonyms: Cytoplasmic protein NCK2, GRB4, Growth factor receptor-bound protein 4, NCKbeta, Nck-2, ...
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Disease relevance of NCK2


High impact information on NCK2

  • These cellular responses can be blocked in a dominant-negative fashion by expression of the isolated Grb4 SH2 domain [2].
  • Here we show that the SH2/SH3 domain adaptor protein Grb4 binds to the cytoplasmic domain of B ephrins in a phosphotyrosine-dependent manner [2].
  • Accordingly, gamma-secretase inhibitors prevented the EphB-induced sprouting of endothelial cells and the recruitment of Grb4 to ephrinB [3].
  • These data provide novel structural insight into LIM domain-mediated protein-protein recognition and demonstrate that the PINCH-Nck2 interaction is an important component of the focal adhesion assembly during integrin signaling [4].
  • Grb4 bound to Bcr-Abl in a variety of systems, both in vitro and in vivo, and is an excellent substrate of the Bcr-Abl tyrosine kinase [1].

Biological context of NCK2


Anatomical context of NCK2

  • Finally, we provide evidence indicating that a fraction of the Nck-2 and/or Nck-1 proteins are associated with the cytoskeleton [8].
  • Although neither protein was transforming on its own, both Nck and Grb4 cooperated with v-Abl to transform NIH 3T3 cells and influenced the morphology and anchorage-dependent growth of wild type Ras-transformed cells [9].
  • In the present study, we report the isolation of Xenopus Grb4 (growth-factor-receptor-bound protein 4), an ephrinB1-interacting protein, and we show that when expressed in Xenopus oocytes, ephrinB1 interacts with Grb4 in the presence of an activated FGFR1 [10].

Co-localisations of NCK2

  • A fraction of Nck-2 co-localizes with FAK at cell periphery in spreading cells [6].

Other interactions of NCK2

  • Additionally, biochemical studies indicate that ILK, through the interaction with PINCH, is capable of forming a ternary complex with Nck-2, an SH2/SH3-containing adapter protein implicated in growth factor receptor kinase and small GTPase signaling pathways [11].
  • The phosphotyrosine peptide binding specificity of Nck1 and Nck2 Src homology 2 domains [12].
  • Furthermore, we show that Nck-2 is capable of recognizing several key components of growth factor receptor kinase-signaling pathways including EGF receptors, PDGF receptor-beta, and IRS-1 [8].
  • Additionally, we have detected a stable association between Nck-2 and IRS-1 that was mediated primarily via the second and third SH3 domain of Nck-2 [8].
  • Suppression of Grb2 or Nck2 results in loss of localization of N-WASP at the activation site and reduced actin polymerization [13].

Analytical, diagnostic and therapeutic context of NCK2

  • Indeed, cell fractionation and fluorescence microscopy studies revealed that the stronger inhibitory potential of the Grb4 SH2 mutant occurred in conjunction with increased nuclear localization of this mutant [5].
  • (3) Several high-affinity bindings were identified for hNck2 SH3 domains by isothermal titration calorimetry [14].


  1. Characterization of Ggrb4, an adapter protein interacting with Bcr-Abl. Coutinho, S., Jahn, T., Lewitzky, M., Feller, S., Hutzler, P., Peschel, C., Duyster, J. Blood (2000) [Pubmed]
  2. The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Cowan, C.A., Henkemeyer, M. Nature (2001) [Pubmed]
  3. Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. Georgakopoulos, A., Litterst, C., Ghersi, E., Baki, L., Xu, C., Serban, G., Robakis, N.K. EMBO J. (2006) [Pubmed]
  4. Structural and functional insights into PINCH LIM4 domain-mediated integrin signaling. Velyvis, A., Vaynberg, J., Yang, Y., Vinogradova, O., Zhang, Y., Wu, C., Qin, J. Nat. Struct. Biol. (2003) [Pubmed]
  5. Grb4/Nckbeta acts as a nuclear repressor of v-Abl-induced transcription from c-jun/c-fos promoter elements. Jahn, T., Seipel, P., Coutinho, S., Miething, C., Peschel, C., Duyster, J. J. Biol. Chem. (2001) [Pubmed]
  6. Nck-2 interacts with focal adhesion kinase and modulates cell motility. Goicoechea, S.M., Tu, Y., Hua, Y., Chen, K., Shen, T.L., Guan, J.L., Wu, C. Int. J. Biochem. Cell Biol. (2002) [Pubmed]
  7. Identification and kinetic analysis of the interaction between Nck-2 and DOCK180. Tu, Y., Kucik, D.F., Wu, C. FEBS Lett. (2001) [Pubmed]
  8. Nck-2, a novel Src homology2/3-containing adaptor protein that interacts with the LIM-only protein PINCH and components of growth factor receptor kinase-signaling pathways. Tu, Y., Li, F., Wu, C. Mol. Biol. Cell (1998) [Pubmed]
  9. Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck. Braverman, L.E., Quilliam, L.A. J. Biol. Chem. (1999) [Pubmed]
  10. Tyr-298 in ephrinB1 is critical for an interaction with the Grb4 adaptor protein. Bong, Y.S., Park, Y.H., Lee, H.S., Mood, K., Ishimura, A., Daar, I.O. Biochem. J. (2004) [Pubmed]
  11. The LIM-only protein PINCH directly interacts with integrin-linked kinase and is recruited to integrin-rich sites in spreading cells. Tu, Y., Li, F., Goicoechea, S., Wu, C. Mol. Cell. Biol. (1999) [Pubmed]
  12. The phosphotyrosine peptide binding specificity of Nck1 and Nck2 Src homology 2 domains. Frese, S., Schubert, W.D., Findeis, A.C., Marquardt, T., Roske, Y.S., Stradal, T.E., Heinz, D.W. J. Biol. Chem. (2006) [Pubmed]
  13. A neural Wiskott-Aldrich Syndrome protein-mediated pathway for localized activation of actin polymerization that is regulated by cortactin. Kempiak, S.J., Yamaguchi, H., Sarmiento, C., Sidani, M., Ghosh, M., Eddy, R.J., Desmarais, V., Way, M., Condeelis, J., Segall, J.E. J. Biol. Chem. (2005) [Pubmed]
  14. Structural insight into the binding diversity between the human Nck2 SH3 domains and proline-rich proteins. Liu, J., Li, M., Ran, X., Fan, J.S., Song, J. Biochemistry (2006) [Pubmed]
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